Combination therapies induce cancer cell death through the integrated stress response and disturbed pyrimidine metabolism

verfasst von

Goetz Hartleben, Kenji Schorpp, Yun Kwon, Barbara Betz, Foivos Filippos Tsokanos, Zahra Dantes, Arlett Schäfer, Ina Rothenaigner, José Manuel Monroy Kuhn, Pauline Morigny, Lisa Mehr, Sean Lin, Susanne Seitz, Janina Tokarz, Anna Artati, Jerzy Adamsky, Oliver Plettenburg, Dominik Lutter, Martin Irmler, Johannes Beckers, Maximilian Reichert, Kamyar Hadian, Anja Zeigerer, Stephan Herzig, Mauricio Berriel Diaz

Abstract

By accentuating drug efficacy and impeding resistance mechanisms, combinatorial, multi-agent therapies have emerged as key approaches in the treatment of complex diseases, most notably cancer. Using high-throughput drug screens, we uncovered distinct metabolic vulnerabilities and thereby identified drug combinations synergistically causing a starvation-like lethal catabolic response in tumor cells from different cancer entities. Domperidone, a dopamine receptor antagonist, as well as several tricyclic antidepressants (TCAs), including imipramine, induced cancer cell death in combination with the mitochondrial uncoupler niclosamide ethanolamine (NEN) through activation of the integrated stress response pathway and the catabolic CLEAR network. Using transcriptome and metabolome analyses, we characterized a combinatorial response, mainly driven by the transcription factors CHOP and TFE3, which resulted in cell death through enhanced pyrimidine catabolism as well as reduced pyrimidine synthesis. Remarkably, the drug combinations sensitized human organoid cultures to the standard-of-care chemotherapy paclitaxel. Thus, our combinatorial approach could be clinically implemented into established treatment regimen, which would be further facilitated by the advantages of drug repurposing.

Organisationseinheit(en)

Institut für Organische Chemie

Externe Organisation(en)

Helmholtz Zentrum München - Deutsches Forschungszentrum für Gesundheit und Umwelt
Technische Universität München (TUM)
National University of Singapore
Institut für Diabetesforschung der Forschergruppe Diabetes e.V.
Ruprecht-Karls-Universität Heidelberg

Typ

Artikel

Journal

EMBO molecular medicine

Band

13

ISSN

1757-4676

Publikationsdatum

09.04.2021

Publikationsstatus

Veröffentlicht

Peer-reviewed

Ja

ASJC Scopus Sachgebiete

Molekularmedizin

Ziele für nachhaltige Entwicklung

SDG 3 – Gute Gesundheit und Wohlergehen

Elektronische Version(en)

https://doi.org/10.15252/emmm.202012461 (Zugang: Offen)